Antibiotics of cephalosporin series are widely used for the treatment of diseases which are caused by general pathogenic bacteria in human beings and animals. Particularly, such antibiotics have been found to be useful for the treatment of diseases caused by bacteria exhibiting resistance to other antibiotics, e.g., penicillin-resistant bacteria; and also for the treatment of penicillin-hypersensitive patients.
In most circumstances, it is desirable to employ antibiotics possessed with broad antibacterial activities, e.g., against both Gram-positive and Gram-negative bacteria. It is well known that the activity of a cephalosporin compound generally depends upon the substituent on the 3- or 7-position of the cephem ring. In this regard, there have been many studies made in developing a variety of cephalosporin antibiotics with such broad spectrum of antibiotic activities by introducing a 7-.beta. acylamido group and various substituents on the 3-position of the cephem ring.
For example, GB Patent No. 1,399,086 discloses cephalosporin derivatives of formula (A): ##STR2## wherein: R.sup.a represents a hydrogen or an organic group;
R.sup.b represents an etherified mono-valent organic group; PA0 B represents S or S.fwdarw.O; and PA0 P represents an organic group. PA0 R.sup.d represents a C.sub.1-4 alkyl, C.sub.3-4 cycloalkyl, furylmethyl or thienylmethyl group; and PA0 R.sup.e represents a hydrogen, or a carbamoyl, carboxymethyl, sulfonyl or methyl group. PA0 R.sup.g and R.sup.h represent a hydrogen or oxygen, or a methyl, carboxyl or protected carboxyl group, respectively; PA0 R.sup.i and R.sup.j represent a hydrogen or oxygen, respectively; PA0 R.sup.k represents a hydrogen or a carboxyl protecting group; PA0 a, b and c are 0 or 1, independently; PA0 X is a hydrogen, a hydroxyl group or ##STR5## Y represents a carbon or nitrogen; and Z represents a halogen, an acetoxy or heterocyclic group. PA0 R.sup.m and R.sup.n represent a hydroxy or substituted hydroxy group independently, or they can link together to form a protected diol; PA0 R.sup.O and R.sup.p represent a hydrogen or a carboxyl protecting group, independently; PA0 R.sup.q represents a hydrogen or a C.sub.1-4 alkyl group substituted with 1 to 3 halogens; and PA0 the dotted line represents a 2-cephem or 3-cephem compound. PA0 R.sup.s represents a hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, acyl, aryl, alkylsulfonyl, arylsulfonyl or heterocyclic group; PA0 R.sup.t represents a hydrogen, an ester group or anion; PA0 R.sup.u represents a hydrogen or a lower alkyloxy group; PA0 X represents S, O, CH.sub.2 or NH; and PA0 A represents a hydrogen or halogen, or a substituted or unsubstituted alkenyloxy or --CH.sub.2 Y wherein Y represents a hydrogen or halogen or a moiety of a cyclic compound. PA0 R.sup.2 and R.sup.3 are, independently, a hydrogen or a hydroxy protecting group, or form together a cyclic diol protecting group; PA0 R.sup.4 and R.sup.5 are, independently, a hydrogen or a carboxyl protecting group; PA0 X and Y are a nitrogen and a carbon atom, respectively, or a carbon and a nitrogen atom, respectively; PA0 R.sup.6 and R.sup.7 are, independently, a hydrogen or an amino, substituted amino, hydroxy, alkoxy, C.sub.1-4 alkyl, carboxyl or alkoxy carbonyl group, or jointly form a C.sub.3-7 cycloalkyl group together with the carbon to which they are attached, when X and Y are a nitrogen and a carbon, respectively, or PA0 R.sup.7 is a hydrogen or an amino group when X and Y are a carbon and a nitrogen, respectively; and PA0 Q is .dbd.CH-- or .dbd.N--.
Stimulated by the discovery of these compounds, there have followed numerous antibiotic compounds having improved efficacy properties with respect to certain microorganisms, especially against Gram-negative bactetia, including those compounds disclosed in GB Patent No. 1,522,140 which have the following formula (B) and exist as a syn isomer or as a mixture of syn and anti isomers wherein the syn isomer is present in an amount of at least 90%: ##STR3## wherein: R.sup.c represents a furyl or thienyl group;
Thereafter, further efforts have been made to prepare new and improved cephalosporin compounds having antibiotic properties against both Gram-positive and Gram-negative bacteria and, as a result, cephalosporin compounds having a modified but similar structure to the formula (A) or (B) have been developed.
For example, Belgian Patent No. 852,427 discloses a cephalosporin antibiotic of formula (A) in which R.sup.a is substituted with various organic groups including 2-aminothiazol-4-yl and the oxygen of oxyamino group is attached to an aliphatic carbon which itself can be substituted with a carboxyl group, and the substituent on the C-3 position is an acyloxymethyl, hydroxymethyl, formyl or optionally substituted heterocyclic thiomethyl group.
Compounds having strong antibiotic activities against some of the Gram-negative bacteria producing .beta.-lactamase in addition to other pathogenic bacteria have been studied to develop certain cephalosporin compounds with .alpha.-carboxy-3,4-substituted benzyl group as the R.sup.b group has been known to show a strong activity against a wide range of pathogenic bacteria.
PCT/JP86/00140 discloses cephem compounds of formula (C): ##STR4## wherein: R.sup.f represents a hydrogen or an amino protecting group;
European Patent Appl. No. 87308525.2 gives a cephem compound of formula (D): ##STR6## wherein: R.sup.l represents a hydrogen or an amino protecting group;
German Patent Application No. 2714880.7 discloses cephalosporin compounds of formula (E): ##STR7## wherein: R.sup.r represents a hydrogen, or a substituted or unsubstituted alkyl, acyl, arylsulfonyl, alkylsulfonyl or amino protecting group;